lecture 3 Flashcards
Chromosomal Abnormalities
- alterations in quality or quantity of genetic material
- 50% of spontaneous miscarriages
- due to errors during cell division or mutagenic and ionizing radiation
polymorphic phenotype syndromes
- due to insertions, deletions of genetic errors
- doesnt follow mendels law
- non-curable
Causes of structural autosomal abnormalities
- deletions
- inversions
- translocations
causes numeric autosomal abnormalities
- aneuploidies
- polyploidiesc
causes numerical sex abnormalities
- aneuploidies
Structural autosomal abnormalities
- less frequent than numerical
- due to breakage in one or more chromosomes -> incorrect rejoining of segment or loss/gain of material
-> chromosomal rearrangement - main cause: ionizing radiation and other mutagens
balanced and unbalanced structural autosomal abnormalities
- balanced : complete chromosome set, but rearranged
- unbalanced: additional or missing genetic information
(includes deletions, insertions, duplications of segments)
Gaps and breakages
= areas of DNA thinning
- occur during interphase
- when breakage does not affect the centromere, a smaller chromosome is formed with centromere and acentric breakage
-> smaller chromosome has deletion in chromosome part
-> acentric breakage will disappear in next cell division -> cells with chromosomal deletions
Deletions in structural autosomal abnormalities
- chromosome breaks at one point -> end part of chromosome is lost
- breaks at 2 points -> middle part is lost
- deletion can be small or large
- lost during replication, as the kinetochores attach to centromeres
Duplications in structural autosomal abnormalities
- part of chromosome is duplicated several times
-> unequal cross-over between homologs or non-homologs
-> multiple copies of some genes
inversions in structural autosomal abnormalities
- breakage at 2 different parts -> broken segment is rejoined inverted
- no problems in mitosis
- paracentric inversion: centromere not affected
-> no change in chromosomal morphology -> inversion can only be seen with banding techniques - pericentric inversion: centromere part of inverted segment
-> centromere changes position, possible change in morphology
(submetacentric can become acrocentric)
-> crossing over in inverted segments results in gametes with abnormal chromosomes - final chromosomes have deletions, duplications that are inviable
Translocation in structural autosomal abnormalities
- formation of a new translocated chromosome (derivative chromosome)
- the chromosomes may be homologs or non-homologs
- reciprocal (balanced): no loss or excess of genetic material
- non reciprocal (unbalanced): loss or excess of genetic material
- individuals with reciprocal translocations are phenotypically normal, but gametes may have unbalanced translocated chromosomes
- unbalanced translocation occurs when the offspring gets 1 derivative chromosome from a parent, who carries balanced translocation
robertsonian translocation in structural autosomal abnormalities
- when p arms of 2 acrocentric chromosomes break, resulting in q arms with sticky ends
-> joining of the 2 q arms results in 1 large chromosome with 2 q arms - number of chromosome decreases by one
-> 2 initial acrocentric chromosomes become 1 meta- or submetacentric chromosome - p arms usually carry redundant genetic material -> loss does not cause clinical symptoms and carriers of rob translocation are phenotypically normal
Ring chromosomes
telomere of each chromosome arm has been deleted -Y broken arms have reunited in ring formation
- breaks are lost -> deleted genetic material
- can result in abnormal gametes
- can still cause syndromes
isochromosomes
1 arm is duplicated -> 2 arms of equal length with same loci
the other arm is deleted
-> chromosome with 2 equal identical arms (either 2 q or p arms)
- excess copies of some genes, loss of some others
dicentric chromosomes
- chromosome with 2 centromeres
- 2 chromosomal breaks (each carries centromere) that are fused together
- unstable -> lost during cell division -> loss of genetic material
47,XY,+13
male with extra chromosome 13 (trisomy 13)
46,XX,5p-
or
46,XX,del(5p)
female with 46 chromosomes, deletion in p-arm of chromosome 5
46,XX,t(2;8)(q21;p13)
female with 46 chromosomes
reciprocal translocation between chromosomes 2 and 8 with breakages in segments q21 and p13
46,XX,inv(10)(p11q13)
female with 46 chromosomes
inversion in chromosome 10 between p11 and q13 (pericentric)
-> pericentric because its between a p and q arm
45,XY,-14,-21,t(14q21q)
or
45,XY,der(14;21)
male with deletions in chromosome 14 and 21
carrier of reciprocal translocation between q arm of Chrom 14 and 21 (derivative chromosome)
46,XX/47,XX,+8
female with mixed cells (mosaicism)
normal cells and cells with extra chromosome 8 (trisomy 8)
Cri du chat syndrome
structural autosomal abnormality
- 1/35,000
- deletions in p arm of Chromosome 5 5p-
- can be terminal or interstitial
- can be inherited due to unbalanced translocation
- terminal deletion: loss of end of chromosome
- interstitial deletion: results after two breaks in the middle of the chromosome are induced
- abnormal tongue, laryngeal growth, mental retardation, elongated face, facial dysmorphism, strabismus, gastrointestinal and cardiac complications, etc
- size of deletion varies among individuals -> the larger the deletion, the more severe the intellectual disability and developmental delay
Beckwith-Wiedemann Syndrome (BWS)
structural autosomal
- 1/13,700
- interstitial deletion of chromosome 11 11p-
- overgrowth, macroglossy, hypoglycemia, umbilical hernia, cancer predisposition, anterior lobe plexus, vascular malformations, organomegaly, etc.
Chromic myelogenous leukaemia (CML)
structural autosomal
. hematologic malignancy: white blood cells dont mature, proliferate in large numbers
- 3rd most frequent type of leukaemia in adults
- reciprocal translocation between chromosome 9 and 22 t(9q22q)
-> philadelphia chromosome - derivative chromosome
- fusion of 2 genes : bcr and abl1
-> chimeric protein BCR/ABL1 : over-activity -> oncoprotein, which induces proliferation, differentiation and survival
Numerical autosomal abnormalities
- most frequent mutations in humans
- due to failure of homologs to separate during anaphase in cell division
- mostly in meiosis, but can occur in mitosis as well
- phenotype varies (nr and type of chromosome)
- abnormal nr of chromosomes in a cell increases the risk of having more abnormalities in the forthcoming cell divisions
- only 3 disorders are viable: trisomy 21, trisomy 13 and trisomy 18
- various mechanisms:
– non-disjunction
– delay during anaphase
– polyploidization
Non-disjunction (numerical autosomal)
- most important mechanism
- chromosomes remain together during anaphase -> move toward the same pole
- mosaic cells: normal cells (2n), trisomic cells (2n+1) and monosomic cells (2n-1)
-> aneuploidy: excess or lack of small number of chromosomes - meiosis 1:
homologs dont separate -> 2 gametes with n+1 (trisomic zygotes) and 2 gametes with n-1 (monosomic zygotes) - meiosis 2:
sister chromatids dont separate -> 1 gamete with n+1, 1 gamete with n-1, 2 gametes with n (normal)
delay during anaphase (numerical autosomal)
- chromosome moves toward pole with delay
-> aneuploidies
polyploidization (numerical autosomal)
- homologs appear in cells more than 2 times -> presence of multiple series of homologous chromosomes
- polyploidy: any multiple of basic haploid chromosome number other than the diploid number -> more than 2 sets of chromosomes
- only triploidy (3n) has been observed in humans
- incompatible with survival or normal human development
Trisomy 21 (downs)
- 1/800
- life expectancy over 30 years
- round face, upward slant eyes, epicanthal folds, brushfield spots on iris, enlarged tongue, minor ear anomalies
- mental and developmental retardation, hypotonic muscles, short hands and fingers, congenital heart disease, alzheimers, leukemia risk, premature aging
- females can be fertile, males are infertile
- correlation to mother’s age (accumulation of mutations over the years in ova)
- 95% is trisomy 21
due to meiotic non-disjunction (95% during meiosis I in ova, 5% in meiosis I in sperm) - non-inheritable
- 47,XX,+21)
- 4% due to robertsonian translocation
- 1% mosaic down syndrome
- partial trisomy
Robertsonian translocation in trisomy 21
- 4% of trisomy 21 cases
- individuals with 46 chromosomes, one chromosome from rob translocation between q arm of 21 and q arm of a acrocentric chromosome (usually 14 or 22)
-> derivative chromosome replaces on of the normal acrocentric chromosome -> patient is trisomic for 21q
** 46,XX or 46,XY,-14,t(14q21q)**
- no correlation with mothers age
- increased risk when mother (or father) is carrier of rob translocation t(14q21q)
- carrier has 45 chrom -> chrom 14 and 21 are lost, but replaced by the derivative chromosome 45,XX or 45,XY,-14,-21,t(14q21q) but phenotypically normal
- 6 types of gametes formed by carrier:
3 are not viable -> unbalanced
3 are viable -> normal, balanced (gives rise to a carrier) or unbalanced (gives rise to trisomy 21q, when it has the chrom with translocation and one chrom 21)
mosaic down syndrome
- 1% of the cases
- patients come from zygotes that have trisomy 21
- milder phenotype
- high diversity in the phenotypes due to variable proportion of trisomy cells in the embryo during first stages of development -> more trisomic cells, more severe phenotypes
a) error in mitotic division of normal blastocyst (non-disjunction) -> trisomic cells
b) error in mitotic division of trisomic blastocyst (loss of chromosome) results in normal cells
46,XX/47,XX,+21 or male
partial trisomy in down syndrome
- rare
- formed by trisomy in segment of q arm in chromosome 21
- region found in chromosome banding area q22 and contains 50-100 genes (incl. enzymes for purines, superoxide dismutase ans alpha-crystallin)
Edward’s syndrome
47,XX,+18 or 47,XY,+18
- trisomy 18
- 1/5,000
- errors during gametogenesis
- 5% mosaic trisomy 18: milder symptoms
- rare partial trisomy18: translocation of q arm
- more frequent during conception but 95% result in spontaneous abortions
- embryos dont survive more than few months, rare cases have survived 15 years
- mental and developmental retardation, heart problems, abnormal kidney function, short sternum, micrognathia, dysplasia in ears
Patau syndrome
47,XX,+13 or 47,XY,+13
- 1/16,000
- errors during gametogenesis
- 20% partial trisomy 13: translocation of segment (sometimes inherited)
- rare mosaic trisomy 13: milder symptoms
- embryos dont survive more than 6 months
- mental retardation, abnormal development, heart problems, facial dysplasia, urogenital system problems, cleft lip and palate, polydactylyl
Abnormalities Sex chromosomes
- most common in humans
- either structure or number
- in all sex cells or mosaic form
- most common trisomies: XXY, XXX, XYY
- most common monosomy: X (turner syndrome)
Mosaicism
- due to abnormal mitotic division during initial stages of embryogenesis
- different number of chromosomes in different cells -> genetically different cell lines, that arise from a single zygote
- usually monosomies or trisomies
- autosomal or sex chromosomes
